Summary: The Section on Human Biochemical Genetics studies selected inborn errors of metabolism to provide insight into cellular mechanisms and care for neglected groups of rare disease patients. 1. Members of the Section admitted approximately 50 individuals with cystinosis as inpatients or outpatients to the NIH Clinical Research Center, documenting the beneficial effects of oral cysteamine therapy with respect to growth, renal function, and ophthalmic abnormalities. In addition, they published an exposition of the late complications of cystinosis, comprehensively described the disease for geneticists in GeneReviews, collaborated on an investigation of autophagy in cystinotic cells, addressed a national meeting of the cystinosis advocacy group, and continued to work to bring cysteamine eyedrops to New Drug Approval by the FDA. The Section serves as the world authority on cystinosis, responding to scores of inquires every year from patients and physicians throughout the world. 2. The Section continued its investigations into alkaptonuria, a disorder of accumulation of homogentisic acid due to deficiency of homogentisate 1,2-dioxygenase. Members of the group described the mutation spectrum in homogentisic acid oxygenase (HGD), the gene involved in alkaptonuria. In collaboration with the Clinical Center's Rehabilitation Medicine Department, members of the Section completed a randomized clinical trial of nitisinone, a powerful inhibitor of the enzyme that produces homogentisic acid, using hip range of motion as the primary outcome parameter. Forty subjects were enrolled, and the results, demonstrating the safety of nitisinone and its consequent hypertyrosinemia, are being prepared for publication. Members of the Section continue to provide their expertise for patients and physicians throughout the world. 3. The Section remains the only center in the world investigating both the clinical and basic aspects of Hermansky-Pudlak syndrome (HPS), a rare disorder of oculocutaneous albinism and bleeding due to abnormal formation of intracellular vesicles, including melanosomes in melanocytes and dense bodies in platelets. There are 8 genetic subtypes of this disease and, by investigating more than 250 affected individuals, members of the Section have determined that the fatal pulmonary fibrosis of HPS occurs only in subtypes 1 and 4. In basic studies, the Section has identified the promoter regions of HPS genes by phylogenetic footprinting and has described the abnormal cytokine patterns in HPS alveolar macrophages. The group has also characterized the disease in patients of African American and Indian ancestry. Physicians in the Section have completed a randomized, placebo-controlled clinical trial of the antifibrotic agent, pirfenidone, to combat the fatal pulmonary fibrosis of HPS. The outcome parameter is change in forced vital capacity;interim analysis recently demonstrated no difference between the treated and untreated groups, and the trial is being stopped because of futility. Nevertheless, an enormous amount of information was collected regarding the natural history of the disease, the safety of pirfenidone, and the appropriate patient population and study design for a future clinical trial. In an ancillary pilot study, patients with severe, fatal pulmonary fibrosis are being treated with a 5-drug regimen in an attempt to arrest their disease;three patients have been enrolled. In parallel with these clinical trials, Section physicians are investigating the etiology of the lung fibrosis through studies of cytokine markers and surface glycoproteins in blood and pulmonary lavage fluid. Elevations in MCP1, MUC-1, and galectin-3 have been found to signal a decline in pulmonary function. Members of the Section have written a review and book chapter on HPS and other disorders of lysosome-related organelles. 4. The Section has mapped the gene for Gray Platelet Syndrome (GPS), a disorder in which platelet alpha granules are absent and patients suffer from a bleeding diathesis. Candidate genes continue to be sequenced. 5. An ongoing clinical protocol investigates Autosomal Recessive Polycystic Kidney Disease and Congenital Hepatic Fibrosis (ARPKD/CHF) to define the natural history and determine outcome parameters for future therapeutic intervention. Results include rates of progression of kidney growth, liver growth, and decline in renal function, frequency of systemic and portal hypertension, inappropriate elevation of vasopressin, measurements of renal tubular function, and delineation of mutations in the PKHD1 gene. More than 100 patients with ARPKD/CHF and related ciliopathies have been evaluated in this study. The group has published papers describing the radiologic features of ARPKD/CHF, three cases of patients with MKS3 gene mutations but clinical features of other ciliopathies, several patients with COACH/Joubert syndrome and congenital hepatic fibrosis, and a comprehensive review of CHF for geneticists in GeneReviews. 6. Members of the Section characterized the oral and craniofacial findings in children with the premature aging disorder, Hutchinson-Gilford Progeria Syndrome. 7. Members of the Section continue to investigate disorders of vesicle formation and trafficking such as Chediak-Higashi disease (CHD) and Griscelli syndrome. CHD, a disorder characterized by large intracellular granules and a tendency toward fatal infections, is extremely rare, but the Section has now investigated 10 patients, documented a genotype-phenotype correlation, and written the definitive review of the disease for geneticists in GeneReviews. 8. Members of the Section continue to investigate disorders of sialic acid metbolism. A collaboration between the Section and the Cell Biology of Metabolic Disorders Unit resulted in the demonstration that the dominant allele in sialuria, responsible for uncontrolled synthesis of sialic acid by GNE, can be silenced by allele-specific RNA interference. Members of the Section have also written the definitive review on sialic acid storage diseases for GeneReviews. 9. Section investigators have contributed to the description of a new genetic disorder of epilepsy, ataxia, sensorineural deafness and renal tubulopathy due to mutations in KCNJ10, a paper on the use of glyceryl triacetate for Canavans disease, a comprehensive review of 3-methylglutaconic aciduria for GeneReviews, and editorials on Wilson Disease and on Garrods concept of chemical individuality. 10. In collaboration with the Office of Rare Disease Research and the NIH Clinical Center, the Section has spearheaded a new Undiagnosed Diseases Program. This initiative aims to provide answers to patients with mysterious conditions that have long eluded diagnosis, and to advance medical knowledge about rare and common diseases. To date, the Program has received more than 2250 inquiries and 900 sets of medical records from throughout the country. The Program has accepted more than 160 patients and admitted approximately 90, providing state-of-the-art clinical investigations in every case, and solving several diagnostic dilemmas.